The long-term goal of this project is to understand how the neurotrophin BDNF (brain derived neurotrophic factor) influences hippocampal excitability. The project was initially motivated by the identification of robust BDNF expression in dentate gyrus granule cell axons, the mossy fibers. We then showed that BDNF increased glutamatergic transmission from mossy fibers to their major target, CA3 pyramidal cells, and that hyperexcitability could result. This led us to suggest that BDNF might be a reason why the hippocampus has an important role in learning and memory, but the hippocampus is also susceptible to seizures. In the second project period, we began to evaluate the potential role of BDNF in the hippocampal effects of estrogen. This direction was based on new data showing that estrogen has a response element on the BDNF gene. We showed that BDNF is upregulated by estrogen in the mossy fiber pathway, and estrogen induced BDNF-like effects on mossy fiber transmission. This led us to suggest that BDNF regulation by estrogen may explain the positive effects of estrogen on cogntive function, and also might explain why estrogen has been reported to have proconvulsant actions under some conditions. In the current project, we have turned our attention to the ways physiological levels of estrogen can increase excitability in hippocampus, whether these actions are mediated by BDNF, and consequences for seizure susceptibility. This direction was facilitated by progress during the previous period of funding, when an estrogen replacement strategy was developed for ovariectomized rats that would precisely simulate the normal rise in estradiol that occurs during the preovulatory period. We now can use ovariectomized rats to specifically address the role of estrogen, and do so in a way that is most relevant to the intact animal. Based on preliminary data, we hypothesize that the normal rise in estrogen during the ovarian cycle improves hippocampal function by BDNF-dependent actions on the trisynaptic circuit, the fundamental pathway for information processing in hippocampus. Seizure activity does not normally develop, because estrogen induces vascular endothelial growth factor (VEGF) at the same times as it induces BDNF. We have found that estrogen increases VEGF in hippocampus, and exposure of hippocampal slices to VEGF reduces transmission along the trisynaptic circuit and blocks epileptiform activity. These new data suggest that VEGF could control increased excitability induced by estrogen and BDNF. We will now address the hypothesis that BDNF induction by estrogen increases pyramidal cell activation, and the induction of VEGF by estrogen ensures that seizures are prevented.